Digoxin toxicity is a common and important cause of adverse drug events in the elderly US population. The serum and central nervous system (CMS) concentrations of digoxin are affected by p-glycoprotein (P-gp), which regulates gastrointestinal absorption, renal elimination, and CMS penetration of digoxin. The variability in P-gp activity caused by either genetic mutation or concomitant medications has not been studied in a population receiving digoxin clinically. Advancing knowledge of the role of P-gp in clinical digoxin toxicity will assist in elucidating the etiology of toxicity, which may ultimately lead to interventions to reduce the risk of digoxin toxicity. The primary aim of the proposed case-control study is to examine the relationship, in an elderly patient population, between clinical digoxin toxicity and genotypic differences in the multi-drug resistance-1 (MDR1) gene which encodes P-gp. The second aim is to characterize the effect of concomitant drug therapy with P-gp inhibition activity. In addition to improving the safety of digoxin, the - Pharmacoepidemiology study will foster career development in a promising young investigator. The results may advance the safety of several therapeutic agents through understanding the biology of P-gp.